Session: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Poster III
Hematology Disease Topics & Pathways:
AML, Diseases, Therapies, Combinations, Biological Processes, Technology and Procedures, Myeloid Malignancies, Clinically relevant, NGS
Methods: Outcomes of 30 APL patients treated with ATRA or ATRA plus ATO were compared with outcomes predicted by CBM (Table 1). Genomic data from 6 publications (Table 2) derived from whole exome sequencing (WES), targeted next-generation sequencing (NGS), copy number variation (CNV) and/or karyotype data were used. All data was anonymized, de-identified and exempt from IRB review. The available genomic data for each profile was entered into the CBM which generates a patient-specific disease protein network model using PubMed and other online resources. The CBM predicts the patient-specific biomarker and phenotype response of a personalized diseased cell to drug agents, radiation and cell signaling. Disease biomarkers that are unique to each patient were identified within the protein network models. ATO and ATRA were simulated on all 30 patient cases. The treatment impact was assessed by quantitatively measuring the drug’s effect on a cell growth score which is a composite of the quantified values for cell proliferation, survival, and apoptosis, along with the simulated impact on each patient-specific disease biomarker score. Each patient-specific model was also digitally screened to identify response to ATO and ATRA.
Results: The CBM correctly predicted the response to ATO and ATRA in 28 of 30 cases. The overall prediction accuracy was 93% with a PPV of 100%, NPV of 60%, sensitivity of 93%, and specificity of 100%. In 2 of 30 patients who did not respond to ATO and ATRA, the CBM identified clinically relevant deletions to EZH2, KMT2E, and HIPK2 genes. All three genes are located on chromosome 7 and these non-responders had monosomy 7.
Conclusions: The Cellworks Omics Biology Model predicted response to ATO and ATRA in APL patients harboring PML-RARA fusions. Predicting non-response to ATO and ATRA in patients with PML-RARA fusion up-front could prevent ineffective treatment, avoid unnecessary adverse events and reduce treatment costs. Additionally, computational modeling can identify new mechanisms of resistance and suggest alternative regimens for non-responding patients by targeting the patient-specific disease biomarkers unique to each.
Disclosures: Howard: Servier: Consultancy, Other: Speaker; Boston Scientific: Consultancy; Sanofi: Consultancy, Other: Speaker; EUSA Pharma: Consultancy; Cellworks: Consultancy. Nair: Cellworks Research India Private Limited: Current Employment. Grover: Cellworks Research India Private Limited: Current Employment. Tyagi: Cellworks Research India Private Limited: Current Employment. Kumari: Cellworks Research India Private Limited: Current Employment. Prasad: Cellworks Research India Private Limited: Current Employment. Mitra: Cellworks Research India Private Limited: Current Employment. Lala: Cellworks Research India Private Limited: Current Employment. Azam: Cellworks Research India Private Limited: Current Employment. Gupta: Cellworks Research India Private Limited: Current Employment. Mohapatra: Cellworks Research India Private Limited: Current Employment. G: Cellworks Research India Private Limited: Current Employment. Mundkur: Cellworks Group Inc.: Current Employment. Macpherson: Cellworks Group Inc.: Current Employment. Kapoor: Cellworks Research India Private Limited: Current Employment.
See more of: Oral and Poster Abstracts